The police investigate a series of deaths related to people who all appear to have committed suicide by taking a poisonous pill. They turn to their unofficial consultant, Sherlock Holmes, who deduces various elements pointing to a serial killer. Meanwhile, Holmes is introduced to John Watson, a former soldier who served in Afghanistan, and the pair immediately move into a flat in Baker Street. John Watson slowly gets to know and trust Sherlock despite police officer Sally Donovan (Vinette Robinson) warning him that Holmes is a psychopath and will one day be responsible for murder. Sherlock's brother Mycroft (Mark Gatiss), at first not revealing his identity, arranges a meeting with Watson and asks whether he will spy on Sherlock for money, but John refuses. After a series of incidents, the person responsible for the deaths, a taxicab driver (Phil Davis), reveals that his victims took their own lives by playing a game of Russian roulette with two pills: one fatally poisonous, the other safe. Before Sherlock can play the cabbie's game, John shoots the cabbie from an opposite building. Before he dies, the taxicab driver reveals that "Moriarty" was his sponsor.

Sherlock is hired by an old friend to investigate a mysterious break-in at a bank in the City. He discovers that symbols spray-painted onto an office wall are a coded message intended for an employee of the bank, who is later discovered dead in his flat. The next day, a journalist is killed and the same symbols are found nearby. Sherlock and John follow a trail of clues that link the two dead men to a Chinese smuggling ring, who are trying to retrieve a valuable item that one of the dead men stole. Sherlock eventually cracks the coded message based on Suzhou numerals and a book cipher, but not before John and his date, Sarah, are kidnapped by the criminals, who believe that John is Sherlock. Sherlock rescues them, but the leader of the gang escapes. Later, the leader of the gang is in communication with her superior, who is identified by the initial "M". She is then shot by a sniper.

Sherlock is commissioned by Mycroft to investigate the suspicious death of a government employee, who was working on a top-secret defence project: the Bruce-Partington Project.^[12] After rejecting the case and handing it over to John, Sherlock begins to be taunted by a criminal who puts his victims into explosive vests and sets Sherlock deadlines to solve the apparently unrelated cases, which include a twenty-year-old cold case involving the shoes of a drowned boy, the disappearance of a businessman, the death of a TV personality, and the assassination of a museum security guard by the "Golem". As Sherlock solves the cases, he finds links between them. After clearing up the original case regarding the government employee, Sherlock tries to force his unseen adversary to reveal himself. Near the end of the episode, Sherlock and "Jim Moriarty" (Andrew Scott) reach a standoff, where Jim reveals that he is responsible for the crimes. In the final seconds, Sherlock Holmes points his gun at a bomb on the floor that had been strapped to John.

Moriarty chooses to let Sherlock and John go after receiving a phone call. Some time later, Mycroft hires Sherlock and John to retrieve compromising photos of a minor royal, which are held on the camera phone of Irene Adler (Lara Pulver), a ruthless and brilliant dominatrix who also trades in classified information extracted from her rich and powerful clients. Sherlock obtains Adler's phone, but discovers it is booby-trapped and requires a code to disarm it. When Adler discovers that the CIA are on her trail, she disappears and is then apparently killed, only to reappear to ask John to get her camera phone back from Sherlock. Weeks later when the coast is clear, Adler tricks Sherlock into deciphering a coded message on her phone which she obtained from another well-connected client. She sends the message to Moriarty, who in turn uses it to foil a British counter-terror operation. She almost succeeds in blackmailing Mycroft, but Sherlock finally cracks the password for the phone, leaving Adler without the protection she needs to survive. The episode concludes as Mycroft tells John that she has been killed by a terrorist group in Pakistan, while in fact she was secretly rescued by Sherlock.

Sherlock and John are contacted by Henry Knight (Russell Tovey), a man traumatised by the death of his father by a monstrous hound on Dartmoor years before. Investigating Dewer's Hollow, a local spot where the beast was allegedly seen, as well as the nearby Ministry of Defence testing site Baskerville, Sherlock and John uncover a conspiracy wherein one of the Baskerville scientists, Dr. Frankland (Clive Mantle), is continuing the work of H.O.U.N.D., an aborted project to create a hallucinogenic gas for military use. Sherlock and John discover that the legendary hound is an ordinary dog used for publicity that the hallucinogenic gas makes appear as a demonic monster. The "hound" that killed Henry's father was actually Frankland wearing a red-lensed gas mask and a T-shirt bearing the logo of the H.O.U.N.D. group. Confronting both the dog and Frankland at Dewer's Hollow, John and Lestrade shoot the dog. Frankland attempts to flee, but dies when he runs into a minefield. In the final scene, Mycroft releases a confined Jim Moriarty.

Moriarty launches a simultaneous heist on the Tower of London, Bank of England, and Pentonville Prison, crimes for which he allows himself to be captured and put on trial. He secures not-guilty by intimidating the jury and visits Sherlock, explaining he still intends to "burn" him, taunting him with a "final problem" for him to solve. He also tries to destroy Sherlock's reputation. The two meet on the roof of a hospital, where Moriarty explains that assassins will kill John, Mrs. Hudson, and Lestrade if Sherlock does not commit suicide; he wants Sherlock to do this to cement his story after explaining that his "god code" was a myth. Moriarty kills himself to force Sherlock to do the same. Sherlock calls John, confesses to being a fraud, states his final "goodbye" and then steps off the roof.

Anderson believes that Sherlock is still alive after the Reichenbach fall. He confides in Lestrade and tells him his theory for his existence. Anderson believes a string of events ranging from Tibet to India to Germany involve Sherlock's assistance, and this is due to Sherlock not being able to stop investigating. Lestrade tells Anderson that Sherlock is definitely dead and goes to visit John, who has moved out of Baker Street following Sherlock's death. Lestrade gives John some of Sherlock's old items, including a video message from John's birthday. In the message Sherlock states that he will see John very soon and tells him to have a good birthday without him as he is 'busy'.

Two years after his reported Reichenbach Fall demise, Sherlock, who has been cleared of all fraud charges against him, returns with Mycroft's help to a London under threat of terrorist attack. He tries to convince John—who has moved on and now has a girlfriend, Mary Morstan (Amanda Abbington)—to help; however, John is angry that Sherlock did not tell him he was alive. Instead, Sherlock enlists Molly to assist him, but when John is kidnapped by unknown assailants and is rescued by Sherlock and Mary, John returns to help find the terrorists and an underground plot to blow up the Houses of Parliament during an all-night sitting on Guy Fawkes Night.

It is John and Mary's wedding day and Sherlock is daunted by the task of delivering a Best Man's speech. As part of the speech, he recounts cases they have worked on including a soldier being stalked and somehow stabbed in a locked shower, a ghost dating women he dubs "The Mayfly Man", the last being part of John's disastrous stag night, among others. Before his speech ends, he realises that a murderer is present among the guests intent on killing John's old friend, Major Sholto. Sherlock saves the targeted guest, and then informs John and Mary of the meaning of the sign of three; namely that Mary is pregnant.

Stolen letters lead Sherlock into conflict with Charles Augustus Magnussen, "the Napoleon of blackmail" who knows the personal weakness of every person of importance in the Western world. During the investigation Sherlock is shot and nearly killed by Mary, who is being blackmailed by Magnussen. After waking up from near-death, Sherlock escapes the hospital and lures Mary to an abandoned building, where he tricks her into revealing her false identity and attempted murder while John is listening nearby. Months later, Sherlock drugs everyone at the Holmes family Christmas party and steals Mycroft's laptop full of state secrets, and he and John take the laptop to Magnussen to trade for all of the files on 'Mary Morstan'. It is revealed that Magnussen keeps no files; it is all in his near-perfect "mind palace". To protect John, Mary, and their forthcoming child, Holmes kills Magnussen in front of Mycroft and several other witnesses, and as a result is sent off on a suicidal assignment overseas. However, he is brought back almost immediately because of a video being broadcast all over England with Jim Moriarty's face asking "Did you miss me?"

Sherlock, under the influence of drugs, enters his mind palace to solve a case from Victorian times about a bride shooting herself in the head and rising from the grave to kill her husband. If he can solve the murder it might lead him to how Moriarty has risen from the grave after similarly shooting himself in the head. He solves the case, and concludes that Moriarty is indeed dead, but "I know his next move".

Sherlock is asked to investigate the mysterious death of a young man, which he solves quickly but he is led into another mystery when a bust of Margaret Thatcher owned by the dead man's father is smashed. Further busts are smashed and Sherlock discovers that the mystery is linked to Mary and her past as a government agent. A figure from her past is bent on revenge in the belief that Mary betrayed him, but it is discovered that the traitor was the secretary of a British Parliamentary member. Mary is killed by the secretary when she jumps in front of a bullet meant for Sherlock. John blames Sherlock for Mary's death, and their relationship is fractured.

Sherlock is contacted by the daughter of entrepreneur Culverton Smith, who she claims has confessed to a murder, but she does not know who the victim was as her father has used a drug on her that inhibits memory. Sherlock deduces that her father is a serial killer and sets out to expose him, but he has returned to narcotics use since Mary's death and unable to clearly distinguish his own thoughts from reality. He confronts and attacks Smith, and John is forced to subdue him. While recovering in the hospital, Smith appears in Sherlock's room, confesses and then tries to kill him. John bursts in just in time to save Sherlock, who reveals that his behaviour up to that point was not just an elaborate ploy to expose Smith, but also fulfilling Mary's last wish for him to "Save John". Later John's therapist reveals that she is actually Sherlock's secret sister, Eurus, and has been using disguises to manipulate both Sherlock and Watson. The episode ends with Eurus firing a shot at John.

Sherlock and Watson – who had been shot with a tranquilliser by Eurus – trick Mycroft into acknowledging her existence. Eurus steps up her attacks on Sherlock, culminating in the bombing of his Baker Street apartment. Sherlock, Watson and Mycroft venture forth to Sherrinford, a maximum-security psychiatric facility where Eurus is housed. Although Mycroft is skeptical at the suggestion that she has escaped, the trio discover that Eurus has compromised the staff and controls the entire Sherrinford asylum. She subjects the trio to a series of ordeals, testing their morals by forcing them to choose which of her victims live and die and ultimately forcing Sherlock to confront the memory of "Redbeard", a childhood friend whose death set in motion events that saw Eurus incarcerated. Realising that she will continue to test him until someone he cares for dies, Sherlock tries to connect with her on an emotional level, offering her the love and relationship with a brother that she never had, and Eurus stands down. Sherlock and Watson return to the Baker Street apartment, where they find another message from Mary imploring them to stay together. A time lapse montage shows them rebuilding the Baker Street flat to its original lived-in form before meeting a series of unusual clients.